Platelet activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycerol-3 -phosphorylcholine) is a potent inflammatory phospholipid mediator with a wide variety of biological activities. PAF is generated and released by monocytes, macrophages, polymorphonuclear leukocytes (PMNs), eosinophils, neutrophils, natural killer lymphocytes, platelets and endothelial cells, as well as by renal and cardiac tissues under appropriate immunological and non-immunological stimulation. PAF causes the aggregation and degranulation of platelets at very low concentrations. The potency (active at 10.sup.-12 to 10.sup.-9 M), tissue level (picomoles) and short plasma half life (2-4 minutes) of PAF are similar to those of other lipid mediators such as thromboxane A.sub.2, prostaglandins, and leukotrienes.
While PAF mediates essential biological responses, it also appears to play a role in pathological immune and inflammatory responses. Many published studies have provided evidence for the involvement of PAF in human diseases, including arthritis, acute inflammation, asthma, endotoxic shock, pain, psoriasis, ophthalmic inflammation, ischemia, gastrointestinal ulceration, myocardial infarction, inflammatory bowel diseases, and acute respiratory distress syndrome. Animal models also demonstrate that PAF is produced or increased in certain pathological states. Thus, compounds and/or pharmaceutical compositions which act as PAF receptor antagonists will be useful in the treatment of these and other disease states in which excessive amounts of PAF are present.
Leukotrienes, like PAF, are potent local mediators, playing a major role in inflammatory and allergic responses, including arthritis, asthma, psoriasis, and thrombotic disease. Leukotrienes are straight chain eicosanoids produced by the oxidation of arachidonic acid by lipoxygenases. Arachidonic acid is oxidized by 5-lipoxygenase to the hydroperoxide 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is converted to leukotriene A.sub.4, which in turn can be converted to leukotriene B.sub.4, C.sub.4, or D.sub.4. The slow-reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C.sub.4, D.sub.4, and E.sub.4, all of which are potent bronchoconstrictors. There has been a long established research effort to develop specific receptor antagonists or inhibitors of leukotriene biosynthesis, to prevent or minimize pathogenic inflammatory responses mediated by these compounds. As such, compounds and/or pharmaceutical compositions which inhibit the 5-lipoxygenase enzyme will be useful in the treatment of disease states in which excessive amounts of leukotrienes are present.
Given the significant number of pathological immune and inflammatory responses that are mediated by PAF and leukotrienes, there remains a need to identify new compounds and compositions that exhibit PAF receptor antagonistic activity and/or inhibit the enzyme 5-lipoxygenase (5-LO).